RELATIONSHIPS BETWEEN PROSTANOIDS AND CELLULAR INJURY

我们的目标是确定脂质介体在动脉粥样硬化中的作用 细胞损伤和死亡的过程。我们已经证明了 花生四烯酸(AA)参与循环休克、缺氧、 烧伤和补体介导的(C‘)肺损伤。我们有 还观察到补体介导的二十烷类化合物的刺激 在培养的细胞中形成。此外，短期C‘ 治疗可以增加长期的二十烷类化合物的形成 对适当刺激的反应。其目的是为了刻画 C‘直接刺激细胞内AA代谢的机制 分离的内皮细胞，b)表征C‘的性质 与内皮细胞的相互作用导致长期的 增加二十烷类化合物的释放，以及c)在 内毒素血症模型以确定补体- 介导性增加二十烷类化合物的产生是生理学的 意义。具体研究包括对模式的评估， AA代谢物形成的大小和时间过程 培养的牛和人内皮细胞对C‘， 钙在补体介导的免疫反应中的作用 膜的活化过程、表征 所利用的AA的磷脂来源和表征 磷脂酶A和C在刺激过程中的作用。 其他研究将包括对刺激措施的确定。 补体介导的长期增强的特异性 二十烷类化合物的形成，这种敏化的时间进程， C‘之后二十烷类化合物的生产模式是否 预处理不同于正常细胞，而且长期的 膜磷脂AA含量的变化可能 伴随C‘预处理法。与功能相关的研究 这种现象的重要性将涉及到进行实验 在隔离的肝脏、心脏和血管环中 为确定由以下原因引起的功能变化做好准备 C‘充足或耗尽的动物的内毒素血症。 上述研究将对生化机制进行表征。 通过C‘活化可以增加二十烷类化合物的产生 并将阐明这一现象的生理效应 在一段全球受伤的时期。所获得的数据将为 在理解治疗方法方面的价值 以C‘为特征的临床疾病的管理 激活包括败血症，血液透析引起的肺损伤， 烧伤、肾小球肾炎和各种自身免疫性疾病。

Our goal is to characterize the role of lipid mediators in the processes of cellular injury and death. We have demonstrated arachidonic acid (AA) involvement in circulatory shock, hypoxia, burn injury, and complement-mediated (C') lung injury. We have also observed complement-mediated stimulation of eicosanoid formation in cultured cells. Furthermore, short-term C' treatment can augment long-term eicosanoid formation in response to appropriate stimuli. The aims are to characterized the mechanisms by which C' directly stimulates AA metabolism in isolated endothelial cells, b) characterize the nature of the C' interaction with endothelial cells which results in the long-term augmentation of eicosanoid release, and c) carry out studies in a model of endotoxemia to determine whether complement- mediated augmentation of eicosanoid production is of physiologic significance. Specific studies include assessment of the pattern, magnitude, and time course of AA metabolite formation by cultured bovine and human endothelial cells in response to C', investigation of the role of calcium in the complement-mediated activation process, characterization of the membrane phospholipid sources of the AA utilized, and characterization of the role of phospholipases A and C in the stimulation process. Additional studies will include determinations of the stimulus specificity of the long-term complement-mediated augmentation of eicosanoid formation, the time course of this sensitization, whether the pattern of eicosanoid production after C' pretreatment differs from that in normal cells, and the long-term changes in membrane phospholipid AA content which may accompany C' pretreatment. Studies related to the functional importance of this phenomenon will involve experiments carried out in the isolated perfused liver, heart, and vascular ring preparations to determine functional changes which result from endotoxemia in animals which are either C' replete or depleted. The above studies will characterize the biochemical mechanisms by which C' activation can lead to enhanced eicosanoid production and will elucidate the physiologic effect of this phenomenon during a period of global injury. The data obtained will be of value in the understanding therapeutic approaches to the management of clinical disorders which are characterized by C' activation including septicemia, hemodialysis-induced lung injury, burn injury, glomerulonephritis, and various autoimmune diseases.